ORIGINAL ARTICLE
Annals of Nuclear Medicine Vol. 16, No. 1, 33-38, 2002

Serial change in 123I-MIBG myocardial scintigraphy
in non-insulin-dependent diabetes mellitus
Shigeki NAGAMACHI,*Seishi JtNNOUCHt,*Takeshi KUROSE,** Ryuichi NISHII,*
Keiichi KAWAI,*** Shigemi FtJTAMI,* Shozo TAMURA*and Shigeru MA'rStJKURA***Department of Radiology, **ThirdDepartment of Internal Medicine,and ***CentralResearch Laboratories, MiyazakiMedical College

Purpose: We performed 123I-MIBG (MIBG) myocardial scintigraphy twice in patients with noninsulin-dependent diabetes mellitus (NIDDM) to investigate whether MIBG distribution was
improved by pertinent clinical control. To determine the influential factors for MIBG distribution,
we investigated the association between various clinical parameters and the serial change in MIBG
uptake parameters. Patients and Methods: Twenty NIDDM patients with no cardiac disorders were
evaluated. Planar images were taken at 30 minutes (early) and 3 hours (delayed) after MIBG
injection. The heart-to-upper-mediastinum uptake ratio (H/M) and washout ratio (WR) were
calculated as parameters for estimating cardiac sympathetic function. Patients were divided into
two groups, eight in the improved group and twelve in the unimproved group, according to the serialchange in H/M. The mean interval between the baseline and the follow up study was 2.1 + 0.6 year.
Differences between the means of the laboratory data in patients in both groups were compared forthe baseline and the follow up study by using the paired t-test. As a means of determining theinfluential factors for a serial change of MIBG uptake, Fisher's exact test was performed to evaluate
the association between the serial change in cardiac MIBG parameters and changes in other clinicalparameters, such as blood sugar (BS) control, BS control method (insulin therapy), serum
cholesterol control, and severity of diabetic complications. We also analyzed the association
between the changes in CVR-R (coefficient variance of R-R intervals at rest ECG) or NCV (velocity
of posterior tibial nerve) and those of other clinical parameters. Associations among theseneurological parameters (MIBG parameters, CVR-Rand NCV) were also analyzed. Results: Paired
t-tests showed a significant decrease in fasting blood sugar and fructosamine in the improved groupin the follow up study compared to those in the baseline study. Nevertheless, Fisher's exact test
showed no significant association between FBS, HbAlc, fructosamine and the improvement in
cardiac MIBG uptake. The only significant association was observed between the serial change in
H/M and the BS-control method (insulin therapy). Within the neurological parameters, a significant
association was noted between the serial changes in H/M and CVR-R. Conclusion: Although BS
control was likely to be an important factor, it did not always ameliorate cardiac MIBG uptake.
Based on the significant association between the BS-control method (insulin therapy) and MIBG
uptake change, the severity of diabetes mellitus was likely to be a more influential factor. It wassuggested that cardiac MIBG uptake could improve within the mild stage if controlled by diettherapy or an oral hypoglycemic agent in NIDDM.
Key words: follow-up 123I-MIBG myocardial scintigraphy, NIDDM, serial change
Received February 28, 2001, revision accepted November 1,
2001.
For reprint contact: ShigekiNagamachi,M.D., Departmentof
Radiology,Miyazaki Medical College, Kihara 5200, Kiyotakecho, Miyazaki 889-1692, JAPAN.
E-mail: snagama@post.miyazaki-med.ac.jp

Vol. 16, No. 1, 2002

INTRODUCTION
ALOr~Gwith cardiac denervation, cardiac autonomic neuropathy is a significant prognostic factor for diabetes
mellitus. I-3 Many studies have reported the usefulness ofOriginal Article 33

123I-MIBG (MIBG) scintigraphy in monitoring diabetic
cardiac sympathetic nerve dysfunction. 4-16 Decreases in
MIBG uptake have been reported to correlate with the
body mass index (BMI), systolic blood pressure, disturbed left ventricular diastolic filling, and QT interval
length. Diabetic patients with autonomic neuropathy (AN)have a considerably decreased MIBG uptake when compared to diabetics without AN, 4,6 but few studies havebeen performed to clarify whether a disturbed cardiac
sympathetic nervous system can recover in diabetic patients. In insulin-dependent diabetes mellitus (IDDM),
poor glycemic control constitutes an essential determinant in the progression of MIBG uptake, whereas theimpact of glycemic control on the serial change in MIBG
uptake has not been determined in non-insulin-dependent
diabetes mellitus (NIDDM). Although a few limited studies
with aldose reductase inhibitor have been reported, 1~
the results have not been generally accepted.
The current study was undertaken to clarify how myocardial MIBG distribution changes in a clinical follow-up
of patients with NIDDM and to find the determinant factor
influencing the changes in MIBG distribution. At thesame time, the serial changes in the coefficient variance of
the R-R interval of rest ECG (CVR-R), nerve conducting
velocity of the posterior tibial nerve (NCV), and MIBG
uptake were evaluated.
M A T E R I A L S AND M E T H O D S

Twenty patients, all over 43 years of age and diagnosed
with NIDDM by the criteria of the National Diabetes
Group, were enrolled in this study. All subjects had a low
probability of coronary artery disease based on the absence of cardiovascular symptoms, a normal resting ECG,a normal maximal exercise ECG, and a normal stress2~
myocardial SPECT. Based on echocardiographic analysis, no subjects had evidence of left
ventricular hypertrophy, and all had normal left ventricular function. All subjects agreed to participate in the study
and signed an informed consent form approved by theInstitutional Review Board of Miyazaki Medical College.
To block tracer uptake in the thyroid gland, eachsubject received 10 mg of potassium iodine 2 days before
the investigation and 10 mg daily for 1 or 2 days afterwards. Patients remained on their normal diets and drug
regimens except for drugs that could cause changes in
sympathetic activity. Anterior planar images were obtained 15 minutes (early) and 4 hours (delayed) after 123IMIBG (111 MBq) injection by means of a rotating gamma
camera (ZLC7500, Shimadzu) equipped with a Krypton
collimator. Energy discrimination was provided by a 20%
window centered on the 159 keV photopeak of 1231.
For the semiquantitative analysis, the heart-to-uppermediastinum uptake ratio (H/M) was calculated by theconventional ROI method on both early and delayed
planar images, as previously reported.4,17After correction

34 ShigekiNagamachi, Seishi Jinnouchi, Takeshi Kurose, et al

for the physical decay of 123I,the tracer washout rate fromthe myocardium (WR) was calculated by the following
formula.
WR = early ([H]- [M])- delayed ([H] - [M]) x 100%
early ([H] - [M])
According to the serial change in H/M, we divided all
patients into two groups: those whose H/M values werehigher in the follow-up study than in the baseline study
were placed in the improved group. The patients whose
H/M values were lower in the follow-up study than in thebaseline study were placed in the unimproved group.
Because H/M is affected by the size of the heart, 17 thecardiac chamber size was confirmed by 2~
tobe unchanged between the baseline and the follow-up
study.
The clinical characteristics, the mean laboratory data
values and MIBG parameters in the baseline study for thetwo groups were compared (Table 1). All values areshown as the mean + SD. In each group, means for eachparameter in the baseline study data and the follow-up
study data were compared (Table 2). Scheffe's F-test for
multiple comparisons was applied to detect the statistically significant difference as defined by ANOVA. A
comparison of serial data within one group was performedby means of Wilcoxon's matched-pairs signed-rank test.
A value of p < 0.05 was considered statistically significant.
Non-parametric testing (Fisher's exact test) was also
employed to evaluate whether the serial changes in MIBG
parameters were independent of the change in otherFig. 1 A 58-year-old patient with NIDDM for 13 years. In thefirst study (upper row), myocardial MIBG uptake was not notedon either the early (left) or delayed image (right). HIM was 1.7
on the early and 1.8 on the delayed image. WR was 11.8%. In thefollow-up study 2 years later (lower row), normal myocardial
uptake was noted on both the early (left) and delayed images(right). H/M increased to 3.2 on the early and 3.1 on the delayed
image. WR decreased to 3. l%.

Annals of Nuclear Medicine

Table 1 Comparison of parameters between improved andunimproved group in the baseline study

Fig. 2 A 47-year-old woman with NIDDM for 13 years. In thefirst study (upper row), normal myocardial MIBG uptake wasnoted. The value of H/M was 2.5 on the early (left) and 2.2 on the
delayed image (right). WR was 12.0%. Two years later (lowerrow), myocardial MIBG uptake was unclear on both the early(left) and the delayed images (right). Both uptake parameters
decreased to 1.9 and 1.5. WR was 21.1%.

clinical parameters. That is, we divided all patients into
two categories according to each clinical parameter. Thenthe association between each clinical parameter and thechange in MIBG distribution, whether improved or unimproved, was analyzed. The parameters were age (50_> or50<), gender, number of years from onset (_>10 years or< 10 years), body mass index (BMI), hypertension, orthostatic hypotension, BS-controt, BS-contro] method (insulin therapy), VB12 therapy. The relevance of gtycemic
controls was defined as well-controlled or poorly-controlled according to the change in HbAlc and fructosamine
during the observation period. The severity of both retinopathy and nephropathy was defined as follows: normal
or simple retinopathy was categorized as mild, andpreproliferative or proliferative retinopathy was categorized as severe. Similarly, stages 0 to IIIa nephropathy(Japanese Diabetic Society classification) were categorized as mild and stages IIIb to IV were categorized assevere. In terms of BMI, triglycerides and total cholesterol, we divided patients into improved and unimproved
groups.
Corresponding analyses of clinical parameters and
CVR-R or NCV were also done. In addition, associations
among the serial changes in nerve-condition parameters
were evaluated.
RESULTSThe representative improved case showed a remarkableincrease in cardiac MIBG uptake on both early andVol. 16, No. 1, 2002

Male : Female
Age
Duration
BMI
HbAlc
FBS
T-cho
TG
Fmctosamine
NCV
CV~_R
H/M-E
H/M-D
WR
Neuropathy
Retinopathy
Nephropathy
Hypertension
Hypotension
Insulin
Vitamin B12

Improved(n = 8)

Unimproved(n = 12)

3 :5
58.8 + 10.8
13.0 + 9.1
24.5 + 4.2
8.4_+ 1.4
236.8 + 115.8
234.9 + 42.9
193.1 + 140.7
336.9 + 45.6
42.6 _+6.0
1.3 _+0.8
2.3 + 0.5
2.1 +0.5
25.7 _+10.4
6 (75.0%)
5 (62.5%)
4 (50.0%)
6 (75.0%)
5 (62.5%)
2 (25.0%)
4 (50.0%)

8 :4
56.1 + 7.9
12.7 + 2.5
22.0 + 2.0
7.9 + 1.5
204.4 + 41.6
245.0 + 25.2
180.3 +_51.1
355 ~5_+ 124.1
42.5 + 5.3
1.7 _+0.5
2.4 + 0.3
2.1 +0.4
30.7 + 9.2
12 (100%)
12 (100%)
12 (100%)
7 (58%)
8 (68%)
11 (92%)6 (50%)

Duration: Duration from onset, BMI: Body mass index, FBS:
Fasting blood sugar, T-cho: Total cholesterol, TG: Triglyceride, NCV: Nerve conducting velocity of posterior tibial
nerve, CVR-R:Coefficient variance of R-R interval, H/M-E:
Heart to mediastinal uptake ratio of early image, H/M-D:
Heart to mediastinal uptake ratio of delayed image, WR:
Washout ratio, Hypotension: Orthostatic hypotension, Insulin: Controlled with insulin therapy, Vitamin B~2: Vitamin
B~2 medication

delayed planar images in the follow-up study (Fig, 1). In
contrast, the representative unimproved cases showed anotable decrease in cardiac MIBG uptake in the follow-up
study (Fig, 2).
Regarding as laboratory data, there were no apparent
differences between the improved group and the unimproved group in the baseline study. Prevalence of diabetic
complications and insulin therapy were higher in theunimproved group (Table 1). In the improved group, themean H/M value increased significantly and WR decreased significantly in the follow-up study. Both fasting
plasma glucose and fructosamine significantly decreased.
In the unimproved group, both H/M values significantly
decreased in the follow-up study. Mean BMI, triglyceride, NCV and CVR-R significantly deteriorated (Table 2).
Fisher's exact test showed a significant association
between the serial change in H/M, CVR-~ and insulin
therapy. NCV showed a significant association withtriglyceride control (Table 3). Among nerve-condition
parameters, only the serial change in CVR-R showed asignificant association with H/M (Table 4).

Original Article 35

Table 2 Comparison of parameters between baseline and follow up study
Improved group (n = 8)

H/M-E
HIM-D
WR
NCV (m/sec)
CVR-R
BMI (kg/mz)
HbAtc (%)
Fructosamine
FBS (g/d/)
TG (rag/d/)
T-cho

Unimproved group (n = 12)

baselinefollow up

baselinefollow up

2.3 + 0.5
2.1 +_0.5
25.7 -+ 10.4
42,6 _+6,0
1,5 + 0.8
24.5 +_4.2
8.4+ 1.4
336.9 + 45.6
236.8+115.8
193.1 _+ 140.7
234.9 + 42,9*3.3 + 0.4*2.9 + 0.4'19.6 _+9.1
44.1 + 5.9
2.3 _+1,6
23.9 + 3.4
8.0+ 1.9*292.0 + 58.7
"153.6+70.5
161.8 + 94.6
213.6 _+23.8

2.4 + 0.3
2.1 + 0.4
30.7 + 9.2
42.5 _ 5.3
1.7 +_0.5
22.0 + 2.0
8.1 _+1.5
355,5 + 124.1
204.4+41.6
180.3 + 51.1
245.0 + 25,2

*2.1 + 0.3* 1.7 +-0.5
39.1 + 12.3
*38.3 + 3.8* 1.2 _+0.3*24.6 + 1.7
8.0+2.1
331.5 + 101.3
201.6+68.8*204.6 + 36.5
266.4 + 33.4

H/M-E: Heart to mediastinal uptake ratio of early image, H/M-D: Heart to mediastinal uptake ratio of delayed
image, WR: Washout ratio, NCV: Nerve conduction velocity of posterior tibial nerve, CVR-R:Coefficientvariance of R-R interval, BMI: Body mass index, FBS: Fasting blood sugar, TG: Triglyceride, T-cho: Totalcholesterol, * p < 0.05

Table 3 Association between change of neurological parameters and other clinical parameters
Neurological parameters
H/M-E H/M-D

WR

CVR-R NCV

Age
0.64
0.64 >0.99
Sex
0.36
0.36 >0.99
Duration>0.99 >0.99
0.31
BMI
0.4
0.4
0.06
Nephropathy
0.17
0.17
0.16
Retinopathy >0.99 >0.99>0.99
Hypertension 0.64
0.64 >0.99
Hypotension
0.64
0.64
0.61
TG
0.17
0.17
0.65
T-cho
0.65
0.65
>0.99
BS
0.36
0.36 >0.99
Insulin therapy 0.004* 0.004* 0.17
VB~2 therapy
0.67
0.67 >0.99

0.35
0.34
>0.99 >0.99
>0.99
0.31
>0.99 >0.99
>0.99
0.65
>0.99 >0.99>0.99 >0.99
0.31
0.64
0.14
0.007*
>0.99
0.65
0.61
>0.99
0.007* 0.06
0.64 >0.99

H/M: Heart to mediastinum uptake ratio, E: Early, D: Delayed
WR: Washout ratio, CVR-R: Coefficient variance of R-R interval, BMI: Body mass index, TG: Triglyceride, T-cho: Totalcholesterol, BS: Blood sugar, *: statistically significant

DISCUSSION
The current study demonstrated that cardiac 123I-MIBG
distribution improved in patients with N I D D M . The
result was not in accordance with the previous report,
which stated that diabetic cardiac autonomic neuropathy
is an irreversible complication) 8,19 Three major factors
which could explain the decreased M I B G uptake in
NIDDM were considered l3: suppressed type 1 uptake, an
accelerated release from storage vesicles, and a decreased
number of cardiac sympathetic nerve endings or storage
vesicles. Theoretically, both the first and the second
factors are reversible so that an improvement in MIBG

36

Shigeki Nagamachi, Seishi Jinnouchi, Takeshi Kurose, et al

Table 4 Association among neuronal parameters
H/M-E
H/M-D
WR
CVR-R
NCV

H/M-E H/M-D WR

CVa.R

NCV

0.001"~0.06
0.06
0.007*
0.65

0.007"
0.007*

0.17
0.17
0.3

0.001"
0.06

0.007*
0.65

0.06~ 0 . 3
0.3
~0.14
0.3
0.14

H/M: Heart to mediastinum uptake ratio, E: Early, D: Delayed,
WR: Washout ratio, CVR-R:Coefficient variance of R-R interval, NCV: Nerve conduction velocity of posterior tibial nerve,*: statistically significant

distribution could be established by therapy which improved sympathetic nerve storage vesicle function. The
third factor is irreversible and will continue as the diseaseprogresses. Whether cardiac MIBG uptake improves would
be determined by a balance of the condition of suchfactors.
Nevertheless, the most effective method for improving
MIBG uptake remains unknown. Several glycemic control factors, such as HbAlc or fructosamine, have beenreported to be effectual for regulating both diabetic
m a c r o a n g i o p a t h y and m i c r o a n g i o p a t h y . 2~
Strictcontrol of H b A l c or FBS is known to be effective forprimary prevention of coronary artery disease. 21 Cardiac
microangiopathy is also known to improve with strict
glycemic control, 2~ but improvement of cardiac microangiopathy does not always indicate an improvement
in sympathetic nerve function.
As glycemic control in the improved group was betterat the time of the follow up study than the baseline study,
glycemic control was probably important for the improvement of cardiac M I B G uptake. But some cases
categorized in the unimproved group showed a decreasein H/M despite a marked drop in HbAlc. Because of no

Annals of Nuclear Medicine

significant association between glycemic control and serial change in H/M, normoglycemic condition was unlikely to be the absolute factor for the improvement of
MIBG uptake. Rather, the severity of diabetes was considered to be more important, based on the significant
association between the BS control method (i.e. insulin
therapy) and serial change in MIBG. As most of theunimproved cases need insulin therapy, cardiac MIBG
uptake was suggested to be an irreversible condition.
With the progression of diabetes mellitus, the number ofcardiac sympathetic nerve should decrease and they may
not be repaired by glycemic control. Rigorous glycemic
control, therefore, might be effective only in limited
conditions.
Age, gender, BMI, orthostatic hypotension, cholesterol, triglyceride, retinopathy, and nephropathy were notassociated. Although several studies have demonstrated
that a defect in MIBG uptake is correlated with BMI, 23
HT, 13 and orthostatic hypotension,4 the modification ofthese parameters did not lead to the recovery of cardiac
MIBG uptake. In contrast, one patient in the unimproved
group had new-onset hypertension 13 which is a wellknown pivotal factor. These parameters might be only
deterioration factors for MIBG distribution.
Diabetic cardiac autonomic neuropathy is now treatedby ARI administration, 1~
but it has not been
confirmed to be effective in patients with severe NIDDM.
We had no cases treated with ARI. In the current study, weused the alternate drug vitamin B12,26 but no significant
association with MIBG parameters was noted. Althoughvitamin BI2 acts to heal damaged nerves via various
mechanisms, including acceleration of folic acid metabolism, synthesis of lecithin and acetylcholine, 27,28 it appears ineffectual in repairing destroyed nerves.
As expected, a significant association was noted only
between the changes in H/M and CVR-R among the neurological parameters. Because CVR-R indicates a parasympathetic nerve condition, both factors could behave
similarly.16 In contrast, there was a discrepancy between
the serial change in H/M and conduction velocity of theposterior tibial nerve. Although the severity of peripheral
nerve disorder is known to be associated with diabetic
retinopathy, glycemic control, and the duration of diabetes, 29 the current study showed no correlation between
NCV and these diabetes-related clinical factors, except
for triglycerides. The authors do not yet have an explanation for the significant association between NCV andtriglyceride control.
No association between WR and H/M could be explained as follows: In the case of a severely damaged
cardiac sympathetic nerve, only a little MIBG accumulated on the early images. Consequently, the absoluteamount of tracer, which was washed out between the earlyand delayed images, was small, resulting in a normal WR
value even in severe cardiac autonomic neuropathy.
Regarding cardiac function, there is some disagree-Vol. 16, No. 1, 2002

ment about the correlation between cardiac dysfunction
and decreased 123I-MIBG uptake.16,3~Probably due to theshort follow-up time, LVEF did not change significantly
during the observation period. Longer-term follow up
may reveal a correlation between the change in MIBG
parameters and cardiac function.
In conclusion, abnormal myocardial MIBG uptake of
NIDDM was considered to be reversible under the limited
condition of control by diet therapy or an oral hypoglycemic agent. It would improve in association with pertinent
glycemic control.
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Annals of Nuclear Medicine